Oral Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

Dissecting the cellular defects that lead to activated PI3K δ Syndrome (APDS) reveals differences between APDS1 and APDS2 (#175)

Anthony Lau 1 2 , Julia Bier 1 2 , Tina Nguyen 1 2 , Robert Brink 1 2 , Stuart Tangye 1 2 , Elissa Deenick 1 2
  1. Garvan Institute, Darlinghurst, NSW, Australia
  2. St Vincent’s Clinical School, Faculty of Medicine and Health, UNSW Sydney, Darlinghurst, NSW, Australia

APDS is a rare primary immunodeficiency condition caused by heterozygous gain-of-function mutations in PIK3CD (APDS1), which encodes the leukocyte-restricted p110-delta catalytic subunit of phosphoinositide 3-kinase (PI3K) or heterozygous loss-of-function mutations in PIK3R1 (APDS2), which encodes the regulatory subunit of PI3K. PI3K is activated downstream of many receptors expressed by T and B cells and has been implicated in the control of lymphocyte activation and differentiation. APDS patients have increased PI3K activity that leads to multiple immune manifestations including lymphoproliferation, respiratory tract infections, Th2-related pathologies, impaired Ab responses and autoimmunity.

We previously generated a mouse model of APDS1 (Pik3cdE1020K) in order to dissect the cellular changes that lead to disease in these patients. We demonstrated changes in both T and B cells including increased memory T cells, defective Tfh function, decreased isotype switching and a B cell intrinsic break in tolerance and production of autoantibodies. We have now generated a mouse model of APDS2 (Pik3r1E11SpD) in order to determine whether increased PI3K signalling due to loss of regulatory function causes the same cellular changes. In the Pik3r1E11SpDmice we observed many of the same changes previously observed in Pik3cdE1020K mice, including altered cytokine production and decreased isotype switching. However, we also identified multiple differences between the phenotype of Pik3r1E11SpD and Pik3cdE1020K mice.

Together, these studies reveal that although APDS1 and 2 both cause increased PI3K signalling and result in similar clinical phenotypes, there are distinctions between the way these two types of mutations affect cellular function.